Adachi E.,Kanazawa University |
Hirose-Sugiura T.,Kanazawa University |
Kato Y.,Kanazawa University |
Ikebuchi F.,Kanazawa University |
And 5 more authors.
Pharmacology | Year: 2014
Background/Aim: Hepatocyte growth factor (HGF) plays a role in the regeneration and protection of the kidney, but little information is available concerning the pharmacokinetics of therapeutic treatment with HGF. In this study, HGF was administered after the onset of renal injury, and pharmacokinetic analysis was performed simultaneously with an efficacious dose. Methods: For the study of pharmacodynamics, recombinant human HGF was intravenously administered to rats with glycerol-induced acute kidney injury (AKI). In the pharmacokinetic study, rats subjected to glycerol injection or renal ischemia-reperfusion were used as models of AKI, and rats subjected to 5/6 nephrectomy were used as models of chronic kidney disease (CKD). Results: After intravenous administration of HGF at doses of 0.5-2.0 mg/kg, the elevation of blood urea nitrogen was suppressed, indicating that HGF had a pharmacodynamic effect. However, no significant difference was seen in the pharmacokinetic parameters such as clearance, distribution volume and half-life between the normal, AKI and CKD groups. Conclusion: The intravenous administration of HGF after the onset of renal dysfunction exerted a pharmacological effect on AKI, and renal injury did not affect the clearance of plasma HGF. This unaffected profile may serve as a base for the safety of HGF during therapeutic administration. © 2014 S. Karger AG, Basel.
Dissociation of c-Met phosphotyrosine sites in human cells in response to mouse hepatocyte growth factor but not human hepatocyte growth factor: The possible roles of different amino acids in different species
Ikebuchi F.,Osaka University |
Ikebuchi F.,Kringle Pharma Inc. |
Oka K.,Osaka University |
Mizuno S.,Osaka University |
And 5 more authors.
Cell Biochemistry and Function | Year: 2013
Hepatocyte growth factor (HGF) is essential for embryogenesis, tissue regeneration and tumour malignancy through the activation of its receptor, c-Met. We previously demonstrated that HGF α-chain hairpin-loop, K1 domain and β-chain are required for c-Met signalling. The sequential phosphorylation of tyrosine residues, from c-Met kinase domain to multidocking regions, is required for HGF-signalling transduction. Herein, we provide evidence that the disconcerted activation of c-Met tyrosine regions fails to induce biological functions. When human cells were incubated with 'mouse HGF', kinase domain activation (i.e. phospho-Tyr-1230/34/35) became evident, but the multidocking site (i.e. Tyr-1349) was not phosphorylated, resulting in unsuccessful induction of migration and mitogenesis. The binding ability of mouse HGF α-chain, or of β-chain, to human c-Met was lower than that of human HGF, as evidenced by HGF-chimera assay. Notably, only four amino acid positions in HGF α-chain hairpin-loop and K1 domain and six positions in β-chain differed between human HGF and mouse HGF. The human-specific amino acids (such as Gln-95 in hairpin-loop, Arg-134 in K1 domain and Cys-561 in β-chain) may be important for accurate c-Met assembly and signalling transduction. © 2012 John Wiley & Sons, Ltd.
Mizuno S.,Osaka University |
Ikebuchi F.,Kringle Pharma Inc. |
Fukuta K.,Kringle Pharma Inc. |
Fukuta K.,Osaka University |
And 7 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2011
Hepatocyte growth factor (HGF) has the therapeutic potential to improve renal fibrosis and proteinuria in rodents with chronic kidney disease. In contrast, long-term administration of human HGF to normal rats reportedly elicits proteinuria. Thus, the role of HGF during proteinuria remains contentious. The aim of the present study was to demonstrate that human HGF is antigenic to rodents and that immune complex formation causes proteinuria. We administered either human or rat HGF to normal rats for 28days. Albuminuria was evaluated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The renal phenotypes of the two HGF treatments were examined using histological techniques. Administration of human HGF (1mg/kg per day, i.v.) to rats led to severe albuminuria and glomerular hypertrophy in association with increased blood levels of anti-human HGF IgG and IgG deposition in mesangial areas. Furthermore, an immune complex between human HGF and anti-human HGF IgG stimulated the production of proteinuric cytokines (including transforming growth factor-β) in rat cultured mesangial cells. In contrast, treatment of healthy rats with rat HGF for 4weeks caused neither mesangial IgG deposition nor elevated anti-HGF IgG in the blood. Overall, rat HGF did not provoke albuminuria. We conclude that human HGF produces pseudotoxic effects in normal rat kidneys via an immune complex-mediated pathway, whereas syngenic HGF is safe due to less deposition of glomerular IgG. Our results affirm the safety of the repeated use of syngenic HGF for the treatment of chronic organ diseases, such as renal fibrosis and liver cirrhosis. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.
Kringle Pharma Inc. | Date: 2014-06-03
Pharmaceutical, veterinary preparations for liver diseases, renal disease, nerve system diseases, skin diseases, cardiovascular diseases, cancer; Sanitary preparations for medical use; Central nervous system stimulants; Hair growth stimulant; Antipyretic analgesics; Anti-epileptics; Analeptics; Hypnotic sedatives; General anesthetics; Anti-motion sickness preparations; Pharmaceutical preparations acting on the peripheral nervous system; Local anesthetics; Skeletal muscle relaxants; Anhidrotics; Autonomics; Antispasmodics; Diaphoretics; Pharmaceutical preparations acting on the sensory organs; Ophthalmic preparations; Agents for otic and nasal use, namely, nasal spray preparations, eye washes, eye drops, irrigating solutions for eye use; Treatment for eye infection, macular degeneration, retinopathy, rhinitis, and sinusitis; Pharmaceutical antiallergic preparations; Antihistaminics; Cardiovascular treatment preparations; Cardiotonics; Antihypertensives; Vasoconstrictors; Capillary stabilizers; Cerebral hemorrhage prophylactic preparations; Antiarrhythmic preparations; Diuretics; Pharmaceutical preparations acting on respiratory organs; Respiratory stimulants; Anti-cough drops; Antitussive expectorants; Pharmaceutical preparations acting on digestive organs; Gastrointestinal cleaning agents; Clysters; Evacuants (purgatives); Stomachics and digestives; Pharmaceutical preparations for oral use, and for oral inflammation; Emetics; Pharmaceutical preparations for dental purposes for gingivostomatitis, alveolar abscess, and alveoloclasia; Antacids; Antiemetics; Castor oil for medical purposes; Cholagogues; Hormones for medical purposes; Thyroid and para-thyroid hormone preparations; Mixed hormone preparations; Estrogen preparations; Pancreas hormone preparations; Salivary gland hormone preparations; Androgen preparations; Pituitary hormone preparations; Adrenal hormone preparations; Pharmaceutical preparations acting on uro-genital and anal organs; Oxytocics; Anti-hemorrhoidals; Emmenagogues; Contraceptives; Medicated skin care preparations; Pharmaceutical preparations for purulence; Anti-dermoinfectives; Antimicrobials for dermatologic use; Astringents; Anti-inflammatory agents; Analgesics; Anti-itchings; Talcum powder for medical purposes; Medicated baby oils; Medicated baby powders; Medicated bath preparations; Vitamin preparations for medical purposes; Cod-liver oil drops for medical purposes; Mixed vitamin preparations for medical purposes; Vitamin A preparations for medical purposes; Vitamin C preparations for medical purposes; Vitamin D preparations for medical purposes; Vitamin B preparations for medical purposes; Multi-vitamin preparations for medical purposes; Amino acid preparations for medical purposes; Threonine preparations; Tryptophane preparations; Methionine preparations; Lysine preparations; Royal jelly for medical purposes; Calcium supplements for medical purposes; Chondroitin preparations for medical purposes; Protein and amino acid preparations for medical purposes; Saccharide preparations for treating skin diseases, namely, skin ulcer, injury, burn, scleroderma, dematitis, erythroderma, keratosis, dyschromatosis, and lupus erhthematosus; Mineral preparations for medical use; Anticoagulants; Blood substitutes for human and veterinary use; Blood plasma; Hemostatics; Pharmaceutical preparations affecting metabolism; Antidotes; Enzyme preparations for medical purposes; Lactagogues; Lipotropic factor preparations; Pharmaceutical preparations for the treatment of habitual intoxication; Pharmaceutical preparations for activating cellular function; Tumor suppressing agents; Anti-cancer preparations; Anti-sarcoma preparations; Pharmaceutical preparations for treating physically caused lesions; Pharmaceutical preparations for treating heatstroke; Radiation sickness treating drugs; Pharmaceutical preparations for treating chemically caused disorders, namely, chemical burn, side effect of anticancer drugs, and immunosuppresants; Chlorine-detoxication preparations; Arsenic-detoxication preparations; Benzol-detoxication preparations; Antibiotic preparations; Erythromycin preparations; Chloramphenicol preparations; Colistin-polymixin preparations; Sarkomycin preparations; Streptomycin preparations; Thiolutin preparations; Tetracycline preparations; Trichomycin preparations; Mixed antibiotic preparations; Penicillin preparations; Chemotherapeutics; Antisyphilitics; Antituberculous preparations; Sulfonamide preparations; Antileprotic preparations; Biological preparations for medical purposes; Antitoxic sera; Antitoxins; Mixed biological preparations for medical purposes; Preparations for biological tests for medical purposes; Toxoids; Vaccines; Preparations for destroying parasites; Anthelmintics; Odor neutralizing preparations for use on drugs; Pharmaceutical excipients; Diagnostic preparations for medical use; X-ray contrast agents; Diagnostic reagents for medical use; Diagnostic media for bacteriological cultures for medical use; Radio isotope markers for therapeutic or diagnostic use; Opium alkaloid preparations; Synthetic narcotics; Coca alkaloid preparations; Mosquito-repellent incenses; Germicides and fungicides; Rodenticides; Insecticides; Fumigants; Herbicides, namely, weedkillers; Insect-repellents; Antiseptics. Testing, inspection or research of pharmaceuticals and genetics; Medical research; Consultancy and providing information services in the field of testing, inspection or research of pharmaceuticals and genetics; Consultancy and providing information services in the field of medical research; Providing medical and scientific research information and advice in the fields of pharmaceuticals and genetics.
Kringle Pharma Inc. | Date: 2011-03-25
Topical wound healing medicament containing a recombinant skin growth factor protein for treatment purposes.
Kringle Pharma Inc. | Date: 2011-08-03
An object of the present invention is to provide a drug for promoting the regeneration of tendon-bone junction tissue or ligament-bone junction tissue. The present invention relates to a promoter for regeneration of tendon-bone junction tissue or ligament-bone junction tissue including the following (1) or (2) as an active ingredient: (1) the following (1-a), (1-b), or (1-c)(1-a) HGF protein,(1-b) a partial peptide of HGF protein, the peptide having an effect of promoting regeneration of tendon-bone junction tissue or ligament-bone junction tissue,(1-c) a salt of (1-a) or (1-b);(2) DNA including the following (2-a), (2-b), or (2-c),(2-a) DNA encoding HGF protein,(2-b) DNA encoding a partial peptide of HGF protein, the peptide having an effect of promoting regeneration of tendon-bone junction tissue or ligament-bone junction tissue,(2-c) DNA encoding a protein or a peptide, the protein or the peptide having an effect of promoting regeneration of tendon-bone junction tissue or ligament-bone junction tissue, and the DNA hybridizing with DNA comprising a base sequence complementary to (2-a) or (2-b) under a stringent condition.
Kringle Pharma Inc. | Date: 2013-10-18
Provided are a pharmaceutical composition which enhances the sensitivity of a cancer to a molecular target drug, such as gefitinib and erlotinib, wherein the cancer has resistance to the molecular target drug, and a cancer therapeutic agent effective against a cancer having resistance to a molecular target drug, such as gefitinib and erlotinib. The pharmaceutical composition comprising an HGF-MET receptor pathway inhibitor enhances the sensitivity of a cancer to a molecular target drug, such as gefitinib and erlotinib, even though the cancer has resistance to the molecular target drug. The cancer therapeutic agent comprising a molecular target drug in combination with an HGF-MET receptor pathway inhibitor is effective against a cancer having resistance to the molecular target drug.
Kringle Pharma Inc. | Date: 2010-07-23
A neovascularization promoting composition, a granulation formation-promoting composition and a preventive or curative composition for skin ulcer, comprising a human recombinant HGF wherein five amino acid residues are deleted in the first Kringle domain thereof. The provided compositions of the present invention are useful as a drug capable of promoting granulation formation and neovascularization and being effective in tissue restoration, especially as a preventive and curative agent for skin ulcer.